Research

Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury

Andrew RL Medford¹ , Samantha K Douglas¹ , Sofia IH Godinho¹ , Kay M Uppington¹ , Lynne Armstrong¹ , Kathleen M Gillespie¹ , Berendine van Zyl¹ , Terry D Tetley² , Nassif BN Ibrahim³ and Ann B Millar¹

¹  Department of Clinical Science at North Bristol, University of Bristol Paul O'Gorman Lifeline Centre, Southmead Hospital, Westbury-on-Trym, Bristol, BS10 5NB, UK

²  Lung Cell Biology, National Heart & Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK

³  Department of Pathology, North Bristol NHS Trust, Frenchay Hospital, Frenchay Park Road, Frenchay, Bristol, BS16 1LE, UK

author email corresponding author email

Respiratory Research 2009, 10:27doi:10.1186/1465-9921-10-27

Published:	9 April 2009

Abstract

Background

The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.

Methods

VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.

Measurements and Main Results

VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉ isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF₁₆₅ and VEGF₁₂₁ protein which was increased by LPS (p < 0.05). VEGF₁₆₅ upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05).

Conclusion

These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.